Imatinib is the generic name [International Non-proprietary Name] for the compound 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide of the following formula I
which has been approved, as its mesylate salt, for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Imatinib, its manufacture, its pharmaceutically acceptable salts, e.g. acid addition salts, and its protein kinase inhibiting properties are described in U.S. Pat. No. 5,521,184, which is hereby incorporated by reference. In the context of the present patent application, the term “imatinib” is meant to designated 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide in its free form.
It has to be explained that otherwise the wording “imatinib” designates 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide free base in the US only and that “imatinib” for the rest of the world corresponds to 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide mesylate.
The preparation of imatinib and the use thereof, especially as an anti-tumor agent, are described in Example 21 of European patent application EP-A-0 564 409, which is hereby incorporated by reference.
The monomethanesulfonic acid addition salt of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide (hereinafter “imatinib mesylate”) and a preferred crystal form thereof, e.g. the βcrystal form, are described in PCT patent application WO99/03854, hereby incorporated by reference. Possible pharmaceutical preparations, containing an effective amount of imatinib, e.g. imatinib mesylate, are also described in WO99/03854 and are well known in the prior art.
The present invention is derived from the discovery that imatinib also inhibits breast cancer resistance protein. Breast cancer resistance protein (BCRP) is a member of the ATP-binding cassette (ABC) transporter protein family. Such transporter proteins cause several anticancer drugs to efflux from cancer cells reducing the concentrations of the anticancer agent in these cells and thus reducing or eliminating the desirable anticancer effects of the agent in these resistant cancer cells. BCRP over-expression has been associated with resistance to anticancer agents such as doxorubicin, mitoxanthrone and especially camptothecin analogues and derivatives. In addition, the oral absorption of several therapeutic agents is inhibited by the BCRP ATP pump and inhibition of BCRP with imatinib provides a mechanism to improve the oral absorption of such therapeutic agents.